The ammonium ion (NH.sub.4 +) serves a major role in the maintenance of acid-base balance, but is toxic in high concentrations. By the body it is produced from many precursors (nucleic acids, proteins, amino acids, hexosamines, primary amines) by different reactions, and introduced into the body by exogenous sources such as the break down of dietary proteins by intestinal bacteria.
About 20% of the urea [CO(NH.sub.2).sub.2 ] produced in the body diffuses into the gut where it is converted by bacteria to ammonia and carbon dioxide. The ammonia is absorbed and converted back to urea in the liver by way of the ornithine (urea) cycle, the major pathway for elimination of ammonia. Thus, acute and chronic diseases of the liver impair the ability of the liver to remove ammonia from the body.
Elevated levels of ammonia can easily pass the blood brain barrier causing encephalopathies (degenerative diseases of the brain). One cause of neurogenic encephalopathy is bacterial infections of the urinary tract (e.g. the neurogenic bladder). Another cause is deficient detoxification of ammonia due to acute or chronic liver disease which leads to hepatogenic encephalopathy. An important factor in the pathogenesis of this disease has been identified as exogenous (gastrointestinal) ammonia.
Proteins, nucleic acids, amino acids and hexosamines have long been suggested as other sources of cerebral ammonia. Oxidative deaminations of primary amines (monoamines, diamines and polyamines), glycine catabolism via the glycine cleavage system, deaminations of purines and pyrimidines and glucosamine-6-phosphate, among others, are well known ammonia generating reactions, which may contribute to the steady-state level of brain ammonia.
Dementia of the Alzheimer's Type (DAT) is another type of degenerative brain disease with unknown etiology (although several hypotheses have been postulated). There have been recent reports of not only elevated concentrations of ammonia in the brain of DAT patients, but also reports that ammonia is endogenously generated in excess therein. Hoyer, S., et al., Neurosci. Lett. 117:358-362 (1990). There were two reports that arterial ammonia levels were significantly higher in DAT patients than in appropriately matched control subjects. Fisman, M., et al., Am. J. Psychiatry 142:71-73 (1985); Fisman, M., et al., J. Am. Ger. Soc. 37:1102 (1989). Patients who met the diagnostic criteria of DAT, but had no liver disease, nor urinary tract infections had levels of 208.+-.136 .mu.g ammonia per 100 ml of plasma. The normal range was 20-94 .mu.g/100 ml; 83% of the patients had blood ammonia concentrations above the normal limits. Branconnier, R. J., et al., Am. J. Psychiatry 143: 1313 (1986). Arterio-venous differences of ammonia in patients suffering from advanced DAT, and in patients clinically diagnosed as having incipient dementia, in all probability DAT of early onset, were reported. Healthy volunteers showed an average ammonia uptake by the brain of 72.+-.7 .mu.g.kg.sup.-1.min..sup.-1. In striking contrast, 27.+-.3 .mu.g.kg.sup.-1. min..sup.-1 of ammonia was released from the brains of patients with advanced DAT. Patients with presumed early-onset DAT released 256.+-.162 .mu.g.kg.sup.-1 .min..sup.-1 ammonia into the circulation. These findings suggest excessive ammonia production within the brain, with or without a deficient mechanism of ammonia detoxification. Hoyer, S., et al. Neurosci. Lett. 117:358-368 (1990).
The present invention recognizes hyperammonemia as an important factor in at least the symptomatology and progression of DAT. As further described hereafter, cerebral hyperammonemia may influence those factors which are considered to be hallmarks of DAT.